We request a competitive supplement to our existing GM grant (5RO1 GM049369-16) in response to NOT-OD-09-058. The parent grant under the title "Function and Regulation of the Human Splicing Factor SC35" was designed to study the role of SR proteins in regulated RNA processing, focusing on the following 3 specific aims: 1. Analyze the splicing program during heart development 2. Determine the functional requirement of general and tissue-specific splicing regulators in the heart 3. Study the mechanism of regulated splicing by the synergy between SR proteins and other splicing regulators The funding period of this parent grant is from 7/01/07 to 6/30/2011. We thus have two years remaining. Here we propose an extension of this project via the competitive revision mechanism. The parent grant is my first and long-lasting RO1 since becoming independent, which has been supporting our efforts in decoding the function of SR proteins as a family of RNA binding splicing factors and regulators. Our recent discovery marked a turn of this project, revealing that SR proteins have a direct role in transcriptional elongation and a recent finding in the field indicates that SR proteins can interact directly with the tail of histone 3. Based on these recent advances, we now propose to expand our current project to study the interaction of SR proteins with the genome for functional integration between transcription and RNA processing in mammalian cells. This expanded research program has a clear potential to significantly enhance our mechanistic understanding of SR proteins in development and disease. PUBLIC HEALTH RELEVANCE: The proposed project is designed to determine the role of SR proteins in defining splice site by interacting with the genome, which has potential to reveal disease mechanisms.